document_title: Helicobacter pylori

question_text: helicobacter pylori is implicated as a causative agent in the development

text: Helicobacter pylori

text: Signs and symptoms[edit]

text: Up to 85% of people infected with H. pylori never experience symptoms or complications.[13] Acute infection may appear as an acute gastritis with abdominal pain (stomach ache) or nausea.[3] Where this develops into chronic gastritis, the symptoms, if present, are often those of non-ulcer dyspepsia: stomach pains, nausea, bloating, belching, and sometimes vomiting or black stool.[14][15]

text: Individuals infected with H. pylori have a 10 to 20% lifetime risk of developing peptic ulcers and a 1 to 2% risk of acquiring stomach cancer.[5][16] Inflammation of the pyloric antrum is more likely to lead to duodenal ulcers, while inflammation of the corpus (body of the stomach) is more likely to lead to gastric ulcers and gastric carcinoma.[17][18] However, H. pylori possibly plays a role only in the first stage that leads to common chronic inflammation, but not in further stages leading to carcinogenesis.[12] A meta-analysis conducted in 2009 concluded the eradication of H. pylori reduces gastric cancer risk in previously infected individuals, suggesting the continued presence of H. pylori constitutes a relative risk factor of 65% for gastric cancers; in terms of absolute risk, the increase was from 1.1% to 1.7%.[19]

text: H. pylori has been associated with colorectal polyps and colorectal cancer.[20] It may also be associated with eye disease.[21]

text: Pain typically occurs when the stomach is empty, between meals and in the early morning hours, but it can also occur at other times. Less common ulcer symptoms include nausea, vomiting, and loss of appetite. Bleeding can also occur; prolonged bleeding may cause anemia leading to weakness and fatigue. If bleeding is heavy, hematemesis, hematochezia, or melena may occur.[22]

text: Microbiology[edit]

text:
Helicobacter pylori

Scientific classification

Domain:

Bacteria

Phylum:

Proteobacteria

Class:

Epsilonproteobacteria

Order:

Campylobacterales

Family:

Helicobacteraceae

Genus:

Helicobacter

Species:

H. pylori

Binomial name

Helicobacter pylori(Marshall et al. 1985) Goodwin et al., 1989

text: Morphology[edit]

text: H. pylori is a helix-shaped (classified as a curved rod, not spirochaete) Gram-negative bacterium about 3 μm long with a diameter of about 0.5μm. H. pylori can be demonstrated in tissue by Gram stain, Giemsa stain, haematoxylin–eosin stain, Warthin–Starry silver stain, acridine orange stain, and phase-contrast microscopy. It is capable of forming biofilms[23] and can convert from spiral to a possibly viable but nonculturable coccoid form.[24]

text: H. pylori has four to six flagella at the same location; all gastric and enterohepatic Helicobacter species are highly motile owing to flagella.[25] The characteristic sheathed flagellar filaments of Helicobacter are composed of two copolymerized flagellins, FlaA and FlaB.[26]

text: Physiology[edit]

text: H. pylori is microaerophilic—that is, it requires oxygen, but at lower concentration than in the atmosphere. It contains a hydrogenase that can produce energy by oxidizing molecular hydrogen (H2) made by intestinal bacteria.[27] It produces oxidase, catalase, and urease.

text: Outer membrane. H. pylori possesses five major outer membrane protein  families.[16] The largest family includes known and putative adhesins. The other four families are porins, iron transporters, flagellum-associated proteins, and proteins of unknown function. Like other typical Gram-negative bacteria, the outer membrane of H. pylori consists of phospholipids and lipopolysaccharide (LPS). The O antigen of LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric epithelium.[16] The outer membrane also contains cholesterol glucosides, which are present in few other bacteria.[16]

text: Genome[edit]

text: H. pylori consists of a large diversity of strains, and hundreds of genomes have been completely sequenced.[28][29][30][31][32][33] The genome of the strain "26695" consists of about 1.7 million base pairs, with some 1,576 genes. The pan-genome, that is a combined set of 30 sequenced strains, encodes 2,239 protein families (orthologous groups, OGs). Among them, 1248 OGs are conserved in all the 30 strains, and represent the    universal core. The remaining 991 OGs correspond to the accessory genome in which 277 OGs are unique (i.e., OGs present in only one strain).[34]

text: Transcriptome[edit]

text: In 2010, Sharma et al. presented a comprehensive analysis of transcription at single-nucleotide resolution by differential RNA-seq that confirmed the known acid induction of major virulence loci, such as the urease (ure) operon or the cag pathogenicity island (see below).[35] More importantly, this study identified a total of 1,907 transcriptional start sites, 337 primary operons, and 126 additional suboperons, and 66 monocistrons. Until 2010, only about 55 transcriptional start sites (TSSs) were known in this species. Notably, 27% of the primary TSSs are also antisense TSSs, indicating that—similar to E. coli—antisense transcription occurs across the entire H. pylori genome. At least one antisense TSS is associated with about 46% of all open reading frames, including many housekeeping genes.[35] Most (about 50%) of the 5' UTRs are 20–40 nucleotides (nt) in length and support the AAGGag motif located about 6 nt (median distance) upstream of start codons as the consensus Shine–Dalgarno sequence in H. pylori.[35]

text: Genes involved in virulence and pathogenesis[edit]

text: Study of the H. pylori genome is centered on attempts to understand pathogenesis, the ability of this organism to cause disease. About 29% of the loci have a colonization defect when mutated. Two of sequenced strains have an around 40-kb-long Cag pathogenicity island (a common gene sequence believed responsible for pathogenesis) that contains over 40 genes. This pathogenicity island is usually absent from H. pylori strains isolated from humans who are carriers of H. pylori but remain asymptomatic.[36]

text: The cagA gene codes for one of the major H. pylori virulence proteins. Bacterial strains with the cagA gene are associated with an ability to cause ulcers.[37] The cagA gene codes for a relatively long (1186-amino acid) protein. The cag pathogenicity island (PAI) has about 30 genes, part of which code for a complex type IV secretion system. The low GC-content of the cag PAI relative to the rest of the Helicobacter genome suggests the island was acquired by horizontal transfer from another bacterial species.[28]

text: Pathophysiology[edit]

text: Adaptation to the stomach[edit]

text: To avoid the acidic environment of the interior of the stomach (lumen), H. pylori uses its flagella to burrow into the mucus lining of the stomach to reach the epithelial cells underneath, where it is less acidic.[38] H. pylori is able to sense the pH gradient in the mucus and move towards the less acidic region (chemotaxis).  This also keeps the bacteria from being swept away into the lumen with the bacteria's mucus environment, which is constantly moving from its site of creation at the epithelium to its dissolution at the lumen interface.[39]

text: H. pylori is found in the mucus, on the inner surface of the epithelium, and occasionally inside the epithelial cells themselves.[40]  It adheres to the epithelial cells by producing adhesins, which bind to lipids and carbohydrates in the epithelial cell membrane.  One such adhesin, BabA, binds to the Lewis b antigen displayed on the surface of stomach epithelial cells.[41] H. pylori adherence via BabA is acid sensitive and can be fully reversed by increased pH. It has been proposed that BabA's acid responsiveness enables adherence while also allowing an effective escape from unfavorable environment at pH that is harmful to the organism.[42] Another such adhesin, SabA, binds to increased levels of sialyl-Lewis x antigen expressed on gastric mucosa.[43]

text: In addition to using chemotaxis to avoid areas of low pH, H. pylori also neutralizes the acid in its environment by producing large amounts of urease, which breaks down the urea present in the stomach to carbon dioxide and ammonia.  These react with the strong acids in the environment to produce a neutralized area around H. pylori.[44] Urease  knockout mutants are incapable of colonization. In fact, urease expression is not only required for establishing initial colonization but also for maintaining chronic infection.[45]

text: Inflammation, gastritis, and ulcer[edit]

text: H. pylori harms the stomach and duodenal linings by several mechanisms.  The ammonia produced to regulate pH is toxic to epithelial cells, as are biochemicals produced by H. pylori such as proteases, vacuolating cytotoxin A (VacA) (this damages epithelial cells, disrupts tight junctions and causes apoptosis), and certain phospholipases.[46] Cytotoxin associated gene CagA can also cause inflammation and is potentially a carcinogen.[47]

text:
Colonization of the stomach by H. pylori can result in chronic gastritis, an inflammation of the stomach lining, at the site of infection.  Helicobacter cysteine-rich proteins (Hcp), particularly HcpA (hp0211), are known to trigger an immune response, causing inflammation.[48]
Chronic gastritis is likely to underlie H. pylori-related diseases.[49]

text:
Ulcers in the stomach and duodenum result when the consequences of inflammation allow stomach acid and the digestive enzyme pepsin to overwhelm the mechanisms that protect the stomach and duodenal mucous membranes.  The location of colonization of H. pylori, which affects the location of the ulcer, depends on the acidity of the stomach.[50]
In people producing large amounts of acid, H. pylori colonizes near the pyloric antrum (exit to the duodenum) to avoid the acid-secreting parietal cells at the fundus (near the entrance to the stomach).[16]  In people producing normal or reduced amounts of acid, H. pylori can also colonize the rest of the stomach.

text: The inflammatory response caused by bacteria colonizing near the pyloric antrum induces G cells in the antrum to secrete the hormone gastrin, which travels through the bloodstream to parietal cells in the fundus.[51] Gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well.[52]  The increased acid load damages the duodenum, which may eventually result in ulcers forming in the duodenum.

text: When H. pylori colonizes other areas of the stomach, the inflammatory response can result in atrophy of the stomach lining and eventually ulcers in the stomach.  This also may increase the risk of stomach cancer.[53]

text: Cag pathogenicity island[edit]

text: The pathogenicity of H. pylori may be increased by genes of the cag pathogenicity island; about 50–70% of H. pylori strains in Western countries carry it.[54] Western people infected with strains carrying the cag PAI have a stronger inflammatory response in the stomach and are at a greater risk of developing peptic ulcers or stomach cancer than those infected with strains lacking the island.[16] Following attachment of H. pylori to stomach epithelial cells, the type IV secretion system expressed by the cag PAI "injects" the inflammation-inducing agent, peptidoglycan, from their own cell walls into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic pattern recognition receptor (immune sensor) Nod1, which then stimulates expression of cytokines that promote inflammation.[55]

text: The type-IV secretion apparatus also injects the cag PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the cytoskeleton, adherence to adjacent cells, intracellular signaling, cell polarity, and other cellular activities.[56] Once inside the cell, the CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated tyrosine kinase (TK). CagA then allosterically activates protein tyrosine phosphatase/protooncogene Shp2.[57] Pathogenic strains of H. pylori have been shown to activate the epidermal growth factor receptor (EGFR), a membrane protein with a TK domain. Activation of the EGFR by H. pylori is associated with altered signal transduction and gene expression in host epithelial cells that may contribute to pathogenesis. A C-terminal region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell gene transcription, independent of protein tyrosine phosphorylation.[36][37] A great deal of diversity exists between strains of H. pylori, and the strain that infects a person can predict the outcome.

text: Cancer[edit]

text: Two related mechanisms by which H. pylori could promote cancer are under investigation. One mechanism involves the enhanced production of free radicals near H. pylori and an increased rate of host cell mutation. The other proposed mechanism has been called a "perigenetic pathway",[58] and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such as adhesion proteins. H. pylori has been proposed to induce inflammation and locally high levels of TNF-α and/or interleukin 6 (IL-6). According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF-α, can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in tumor suppressor genes, such as genes that code for cell adhesion proteins.[59]

text: The strain of H. pylori a person is exposed to may influence the risk of developing gastric cancer. Strains of H. pylori that produce high levels of two proteins, vacuolating toxin A (VacA) and the cytotoxin-associated gene A (CagA), appear to cause greater tissue damage than those that produce lower levels or that lack those genes completely. These proteins are directly toxic to cells lining the stomach and signal strongly to the immune system that an invasion is under way. As a result of the bacterial presence, neutrophils and macrophages set up residence in the tissue to fight the bacteria assault.[60]

text: Survival of H. pylori[edit]

text: The pathogenesis of H. pylori depends on its ability to survive in the harsh gastric environment characterized by acidity, peristalsis, and attack by phagocytes accompanied by release of reactive oxygen species.[61] In particular, H. pylori elicits an oxidative stress response during host colonization.  This oxidative stress response induces potentially lethal and mutagenic oxidative DNA adducts in the H. pylori genome.[62]

text: Vulnerability to oxidative stress and oxidative DNA damage occurs commonly in many studied bacterial pathogens, including Neisseria gonorrhoeae, Hemophilus influenzae, Streptococcus pneumoniae, S. mutans, and H. pylori.[63]   For each of these pathogens, surviving the DNA damage induced by oxidative stress appears supported by transformation-mediated recombinational repair.  Thus, transformation and recombinational repair appear to contribute to successful infection.

text: Transformation (the transfer of DNA from one bacterial cell to another through the intervening medium) appears to be part of an adaptation for DNA repair.  H. pylori is naturally competent for transformation.  While many organisms are competent only under certain environmental conditions, such as starvation, H. pylori is competent throughout logarithmic growth.[64]  All organisms encode genetic programs for response to stressful conditions including those that cause DNA damage.[64] In H. pylori, homologous recombination is required for repairing DNA double-strand breaks (DSBs). The AddAB helicase-nuclease complex resects DSBs and loads RecA onto single-strand DNA (ssDNA), which then mediates strand exchange, leading to homologous recombination and repair. The requirement of RecA plus AddAB for efficient gastric colonization suggests, in the stomach, H. pylori is either exposed to double-strand DNA damage that must be repaired or requires some other recombination-mediated event.  In particular, natural transformation is increased by DNA damage in H. pylori, and a connection exists between the DNA damage response and DNA uptake in H. pylori,[64] suggesting natural competence contributes to persistence of H. pylori in its human host and explains the retention of competence in most clinical isolates.

text: RuvC protein is essential to the process of recombinational repair, since it resolves intermediates in this process termed Holliday junctions.  H. pylori mutants that are defective in RuvC have increased sensitivity to DNA-damaging agents and to oxidative stress, exhibit reduced survival within macrophages, and are unable to establish successful infection in a mouse model.[65]  Similarly, RecN protein plays an important role in DSB repair in H. pylori.[66] An H. pylori recN mutant displays an attenuated ability to colonize mouse stomachs, highlighting the importance of recombinational DNA repair in survival of H. pylori within its host.[66]

text: Diagnosis[edit]

text: Colonization with H. pylori is not a disease in and of itself, but a condition associated with a number of disorders of the upper gastrointestinal tract.[16] Testing for H. pylori is not routinely recommended.[16] Testing is recommended if peptic ulcer disease or low-grade gastric MALT lymphoma is present, after endoscopic resection of early gastric cancer, for first-degree relatives with gastric cancer, and in certain cases of dyspepsia.[67] Several methods of testing exist, including invasive and noninvasive testing methods.

text: Noninvasive tests for H. pylori infection may be suitable and include blood antibody tests, stool antigen tests, or the carbon urea breath test (in which the patient drinks 14C—or 13C-labelled urea, which the bacterium metabolizes, producing labelled carbon dioxide that can be detected in the breath).[67][68] It is not known which non-invasive test is more accurate for diagnosing a H. pylori infection, and the clinical significance of the levels obtained with these tests are not clear.[68] Some drugs can affect H. pylori urease activity and give false negatives with the urea-based tests.

text: An endoscopic biopsy is an invasive means to test for H. pylori infection. Low-level infections can be missed by biopsy, so multiple samples are recommended. The most accurate method for detecting H. pylori infection is with a histological examination from two sites after endoscopic biopsy, combined with either a rapid urease test or microbial culture.[69]

text: Prevention[edit]

text: H. pylori is a major cause of certain diseases of the upper gastrointestinal tract. Rising antibiotic resistance increases the need to search for new therapeutic strategies; this might include prevention in the form of vaccination.[70] Much work has been done on developing viable vaccines aimed at providing an alternative strategy to control H. pylori infection and related diseases, including stomach cancer.[71] Researchers are studying different adjuvants, antigens, and routes of immunization to ascertain the most appropriate system of immune protection; however, most of the research only recently moved from animal to human trials.[72] An economic evaluation of the use of a potential H. pylori vaccine in babies found its introduction could, at least in the Netherlands, prove cost-effective for the prevention of peptic ulcer and stomach cancer.[73] A similar approach has also been studied for the United States.[74]

text: The presence of bacteria in the stomach may be beneficial, reducing the prevalence of asthma,[75] rhinitis,[75] dermatitis,[75] inflammatory bowel disease,[75] gastroesophageal reflux disease,[76] and esophageal cancer[76] by influencing systemic immune responses.[75][77]

text: Recent evidence suggests that nonpathogenic strains of H. pylori may be beneficial, e.g., by normalizing stomach acid secretion,[78] and may play a role in regulating appetite, since its presence in the stomach results in a persistent but reversible reduction in the level of ghrelin.[78]

text: Treatment[edit]

text: Once H. pylori is detected in a person with a peptic ulcer, the normal procedure is to eradicate it and allow the ulcer to heal. The standard first-line therapy is a one-week "triple therapy" consisting of proton pump inhibitors such as omeprazole and the antibiotics clarithromycin and amoxicillin.[79] Variations of the triple therapy have been developed over the years, such as using a different proton pump inhibitor, as with pantoprazole or rabeprazole, or replacing amoxicillin with metronidazole for people who are allergic to penicillin.[80] In areas with higher rates of clarithromycin resistance, other options are recommended.[81] Such a therapy has revolutionized the treatment of peptic ulcers and has made a cure to the disease possible. Previously, the only option was symptom control using antacids, H2-antagonists or proton pump inhibitors alone.[82][83]

text: An increasing number of infected individuals are found to harbor antibiotic-resistant bacteria. This results in initial treatment failure and requires additional rounds of antibiotic therapy or alternative strategies, such as a quadruple therapy, which adds a bismuth colloid, such as bismuth subsalicylate.[67][84][85] For the treatment of clarithromycin-resistant strains of H. pylori, the use of levofloxacin as part of the therapy has been suggested.[86][87]

text: Ingesting lactic acid bacteria exerts a suppressive effect on H. pylori infection in both animals and humans, and supplementing with Lactobacillus- and Bifidobacterium-containing yogurt improved the rates of eradication of H. pylori in humans.[88] Symbiotic butyrate-producing bacteria which are normally present in the intestine are sometimes used as probiotics to help suppress H. pylori infections as an adjunct to antibiotic therapy.[89] Butyrate itself is an antimicrobial which destroys the cell envelope of H. pylori by inducing regulatory T cell expression (specifically, FOXP3) and synthesis of an antimicrobial peptide called LL-37, which arises through its action as a histone deacetylase inhibitor.[90][91][92]

text: The substance sulforaphane, which occurs in broccoli and cauliflower, has been proposed as a treatment.[93][94][95] Periodontal therapy or scaling and root planing has also been suggested as an additional treatment.[96]

text: Prognosis[edit]

text: H. pylori colonizes the stomach and induces chronic gastritis, a long-lasting inflammation of the stomach. The bacterium persists in the stomach for decades in most people. Most individuals infected by H. pylori never experience clinical symptoms, despite having chronic gastritis. About 10–20% of those colonized by H. pylori ultimately develop gastric and duodenal ulcers.[16] H. pylori infection is also associated with a 1–2% lifetime risk of stomach cancer and a less than 1% risk of gastric MALT lymphoma.[16]

text: In the absence of treatment, H. pylori infection—once established in its gastric niche—is widely believed to persist for life.[12] In the elderly, however, infection likely can disappear as the stomach's mucosa becomes increasingly atrophic and inhospitable to colonization. The proportion of acute infections that persist is not known, but several studies that followed the natural history in populations have reported apparent spontaneous elimination.[97][98]

text: Mounting evidence suggests H. pylori has an important role in protection from some diseases.[99] The incidence of acid reflux disease, Barrett's esophagus, and esophageal cancer have been rising dramatically at the same time as H. pylori's presence decreases.[100] In 1996, Martin J. Blaser advanced the hypothesis that H. pylori has a beneficial effect by regulating the acidity of the stomach contents.[51][100] The hypothesis is not universally accepted as several randomized controlled trials failed to demonstrate worsening of acid reflux disease symptoms following eradication of H. pylori.[101][102] Nevertheless, Blaser has reasserted his view that H. pylori is a member of the normal flora of the stomach.[103] He postulates that the changes in gastric physiology caused by the loss of H. pylori account for the recent increase in incidence of several diseases, including type 2 diabetes, obesity, and asthma.[103][104] His group has recently shown that H. pylori colonization is associated with a lower incidence of childhood asthma.[105]

text: Epidemiology[edit]

text: At least half the world's population is infected by the bacterium, making it the most widespread infection in the world.[106] Actual infection rates vary from nation to nation; the developing world has much higher infection rates than the West (Western Europe, North America, Australasia), where rates are estimated to be around 25%.[106]

text: The age when someone acquires this bacterium seems to influence the pathologic outcome of the infection. People infected at an early age are likely to develop more intense inflammation that may be followed by atrophic gastritis with a higher subsequent risk of gastric ulcer, gastric cancer, or both. Acquisition at an older age brings different gastric changes more likely to lead to duodenal ulcer.[12] Infections are usually acquired in early childhood in all countries.[16] However, the infection rate of children in developing nations is higher than in industrialized nations, probably due to poor sanitary conditions, perhaps combined with lower antibiotics usage for unrelated pathologies. In developed nations, it is currently uncommon to find infected children, but the percentage of infected people increases with age, with about 50% infected for those over the age of 60 compared with around 10% between 18 and 30 years.[106] The higher prevalence among the elderly reflects higher infection rates in the past when the individuals were children rather than more recent infection at a later age of the individual.[16] In the United States, prevalence appears higher in African-American and Hispanic populations, most likely due to socioeconomic factors.[107][108] The lower rate of infection in the West is largely attributed to higher hygiene standards and widespread use of antibiotics. Despite high rates of infection in certain areas of the world, the overall frequency of H. pylori infection is declining.[109] However, antibiotic resistance is appearing in H. pylori; many metronidazole- and clarithromycin-resistant strains are found in most parts of the world.[110]

text:
H. pylori is contagious, although the exact route of transmission is not known.[111][112]
Person-to-person transmission by either the oral–oral or fecal–oral route is most likely. Consistent with these transmission routes, the bacteria have been isolated from feces, saliva, and dental plaque of some infected people. Findings suggest H. pylori is more easily transmitted by gastric mucus than saliva.[12] Transmission occurs mainly within families in developed nations, yet can also be acquired from the community in developing countries.[113] H. pylori may also be transmitted orally by means of fecal matter through the ingestion of waste-tainted water, so a hygienic environment could help decrease the risk of H. pylori infection.[12]

text: History[edit]

text: H. pylori migrated out of Africa along with its human host circa 60,000 years ago.[114] Recent research states that genetic diversity in H. pylori, like that of its host, decreases with geographic distance from East Africa. Using the genetic diversity data,  researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected by H. pylori before their migrations out of Africa, and it has remained associated with human hosts since that time.[115]

text: H. pylori was first discovered in the stomachs of patients with gastritis and ulcers in 1982 by Drs. Barry Marshall and Robin Warren of Perth, Western Australia. At the time, the conventional thinking was that no bacterium could live in the acid environment of the human stomach. In recognition of their discovery, Marshall and Warren were awarded the 2005 Nobel Prize in Physiology or Medicine.[116]

text: Before the research of Marshall and Warren, German scientists found spiral-shaped bacteria in the lining of the human stomach in 1875, but they were unable to culture them, and the results were eventually forgotten.[100] The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893.[117] Professor Walery Jaworski of the Jagiellonian University in Kraków investigated sediments of gastric washings obtained by lavage from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. His work was included in the Handbook of Gastric Diseases, but it had little impact, as it was written in Polish.[118] Several small studies conducted in the early 20th century demonstrated the presence of curved rods in the stomachs of many people with peptic ulcers and stomach cancers.[119] Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies.[120]

text: Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s, with the visualization of bacteria in the stomachs of people with gastric ulcers.[121] The bacteria had also been observed in 1979, by Robin Warren, who researched it further with Barry Marshall from 1981. After unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their Petri dishes incubating for five days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by stress or spicy food, as had been assumed before.[122]

text: Some skepticism was expressed initially, but within a few years multiple research groups had verified the association of H. pylori with gastritis and, to a lesser extent, ulcers.[123] To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea and vomiting several days later. An endoscopy 10 days after inoculation revealed signs of gastritis and the presence of H. pylori. These results suggested H. pylori was the causative agent. Marshall and Warren went on to demonstrate  antibiotics are effective in the treatment of many cases of gastritis. In 1987, the Sydney gastroenterologist Thomas Borody invented the first triple therapy for the treatment of duodenal ulcers.[124] In 1994, the National Institutes of Health stated most recurrent duodenal and gastric ulcers were caused by H. pylori, and recommended antibiotics be included in the treatment regimen.[125]

text: The bacterium was initially named Campylobacter pyloridis, then renamed C. pylori in 1987 (pylori being the genitive of pylorus,  the circular opening leading from the stomach into the duodenum, from the Ancient Greek word πυλωρός, which means gatekeeper.[126]).[127] When 16S ribosomal RNA gene sequencing and other research showed in 1989 that the bacterium did not belong in the genus Campylobacter, it was placed in its own genus, Helicobacter from the ancient Greek hělix/έλιξ "spiral" or "coil".[126][128]

text: In October 1987, a group of experts met in Copenhagen to found the European Helicobacter Study Group (EHSG), an international multidisciplinary research group and the only institution focused on H. pylori.[129] The Group is involved with the Annual International Workshop on Helicobacter and Related Bacteria,[130] the Maastricht Consensus Reports (European Consensus on the management of H. pylori),[131][132][133][134] and other educational and research projects, including two international long-term projects:

text:
European Registry on H. pylori Management (Hp-EuReg) – a database systematically registering the routine clinical practice of European gastroenterologists.[135]
Optimal H. pylori management in primary care (OptiCare) – a long-term educational project aiming to disseminate the evidence based recommendations of the Maastricht IV Consensus to primary care physicians in Europe, funded by an educational grant from United European Gastroenterology.[136]

text: Research[edit]

text: Results from in vitro studies suggest that fatty acids, mainly polyunsaturated fatty acids, have a bactericidal effect against H. pylori, but their in vivo effects have not been proven.[137]


document_title: Broccoli

question_text: where does broccoli come from in the us

question_tokens: where does broccoli come from in the us

root

text: Broccoli

text: Varieties

text: There are three commonly grown types of broccoli. The most familiar is Calabrese broccoli, often referred to simply as "broccoli", named after Calabria in Italy. It has large (10 to 20 cm) green heads and thick stalks. It is a cool season annual crop.   Sprouting broccoli has a larger number of heads with many thin stalks.  Purple cauliflower is a type of broccoli grown in Europe and North America. It has a head shaped like cauliflower, but consisting of tiny flower buds. It sometimes, but not always, has a purple cast to the tips of the flower buds.

tag: p

text: Other cultivar groups of Brassica oleracea include cabbage (Capitata Group), cauliflower and Romanesco broccoli (Botrytis Group), kale and collard greens (Acephala Group), kohlrabi (Gongylodes Group), Brussels sprouts (Gemmifera Group), and kai-lan (Alboglabra Group).[9] Rapini, sometimes called "broccoli raab" among other names, forms similar but smaller heads, and is actually a type of turnip (Brassica rapa).  Broccolini or "Tenderstem broccoli" is a cross between broccoli and Chinese broccoli. Beneforté is a variety of broccoli containing 2–3 times more glucoraphanin that was produced by crossing broccoli with a wild Brassica variety, Brassica oleracea var villosa.[10]

text: Production

text:
Broccoli production—2014includes cauliflower,[11] millions of tonnes

Country

Production

 People's Republic of China
9.3

 India
8.6

 United States
1.2

 Spain
0.6

 Mexico
0.5

 Italy
0.4

World
24.2

tag: table

text: In 2014, global production of broccoli (combined for production reports with cauliflowers) was 24.2 million tonnes, with China and India together accounting for 74% of the total (table).[11] Secondary producers, each having one million tonnes or less annually, were the United States, Spain, Mexico and Italy (table).[11] The US Department of Agriculture reported that national production just of broccoli in 2014 was 0.95 million tonnes, nearly all of which was grown in California.[12]

text: Cultivation

text:
Broccoli is a cool-weather crop that does poorly in hot summer weather. Broccoli grows best when exposed to an average daily temperature between 18 and 23 °C (64 and 73 °F).[13]
When the cluster of flowers, also referred to as a "head" of broccoli, appear in the center of the plant, the cluster is green. Garden pruners or shears are used to cut the head about an inch from the tip. Broccoli should be harvested before the flowers on the head bloom bright yellow.[14]

text: While the heading broccoli variety performs poorly in hot weather, mainly due to insect infestation, the sprouting variety is more resistant, though attention must be paid to sucking insects (such as aphids), caterpillars and whiteflies. Spraying of bacillus thuringiensis can control caterpillar attacks, while a citronella vase may ward off whiteflies.[15]

text: Pests

text: Mostly introduced by accident to North America, Australia and New Zealand, "cabbage worms", the larvae of Pieris rapae, the small white butterfly are a common pest in broccoli.[16]

text: Nutrition

text:
Broccoli, raw (edible parts)Nutritional value per 100 g (3.5 oz)Energy
141 kJ (34 kcal)
Carbohydrates
6.64 gSugars
1.7 gDietary fiber
2.6 g

Fat
0.37 g

Protein
2.82 g

Vitamins
Quantity %DV†Vitamin A equiv.beta-Carotenelutein zeaxanthin
4% 31 μg3%361 μg1403 μgThiamine (B1)
6% 0.071 mgRiboflavin (B2)
10% 0.117 mgNiacin (B3)
4% 0.639 mgPantothenic acid (B5)
11% 0.573 mgVitamin B6
13% 0.175 mgFolate (B9)
16% 63 μgVitamin C
107% 89.2 mgVitamin E
5% 0.78 mgVitamin K
97% 101.6 μg

Minerals
Quantity %DV†Calcium
5% 47 mgIron
6% 0.73 mgMagnesium
6% 21 mgManganese
10% 0.21 mgPhosphorus
9% 66 mgPotassium
7% 316 mgSodium
2% 33 mgZinc
4% 0.41 mg

Other constituents
QuantityWater
89.3 g

Link to USDA Database entry

Units
μg = micrograms • mg = milligrams
IU = International units

†Percentages are roughly approximated using US recommendations for adults. Source: USDA Nutrient Database

text: As shown on the table, a 100 gram serving of raw broccoli provides 34 kcal and is an excellent source (20% or higher of the Daily Value, DV) of vitamin C and vitamin K. Raw broccoli also contains moderate amounts (10–19% DV) of several B vitamins and the dietary mineral manganese, whereas other essential nutrients are in low content. Broccoli has low content of carbohydrates, protein, fat, and dietary fiber.

text: Boiling broccoli reduces the levels of sulforaphane, with losses of 20–30% after five minutes, 40–50% after ten minutes, and 77% after thirty minutes.[17] However, other preparation methods such as steaming,[18] microwaving, and stir frying had no significant effect on the compounds.[17]

text: Broccoli also contains the carotenoid compounds lutein and zeaxanthin in amounts about 6 times lower than in kale.

text: Taste

text: The perceived bitterness of cruciferous vegetables such as broccoli varies from person to person, but the functional underpinnings of this variation are not known. Some research reports that the gene TAS2R38 may be responsible for bitter taste perception in broccoli.[19] Other factors, such as isothiocyanates and polyphenols, are also likely involved in bitterness perception.[20]

text: Gallery


question_text: where was the pirates of the caribbean 5 filmed

text: Plot[edit]

text: Henry Turner, the twelve-year-old son of Will Turner, boards his cursed father’s ship, the Flying Dutchman, informing his father that the mythical Trident of Poseidon will be able to break his curse, and of his intent to recruit Captain Jack Sparrow to help. Will, however, believes that the trident can't be found and orders Henry to leave, telling his son to let him go and that he loves him and gives Henry his necklace. Will and the Dutchman then disappear under the sea but Henry still vows to find Jack Sparrow and the Trident.

text: Nine years later, Henry is a sailor in the British Royal Navy, but is locked up for attempting mutiny when his ship sails for the supernatural Devil’s Triangle. The ship comes across a shipwreck, the Silent Mary, and are attacked by its ghostly crew led by Captain Salazar. Salazar and his crew kill everyone aboard except Henry. Salazar, seeing a wanted poster of Jack, allows Henry to live so he can deliver a message to Jack that he is coming for him before leaving.

text: In Saint Martin, a young astronomer and horologist named Carina Smyth is sentenced to death for alleged witchcraft, but escapes custody. She briefly crosses paths with Jack, who with his crew tries to steal a bank vault, but accidentally drags the entire bank with them and loses the fortune before crashing the building at the town's exit and escaping. Jack’s crew ends up abandoning him, even Gibbs, who has lost faith in Jack. Depressed, Jack forsakes his magic compass to pay for a drink, subsequently freeing Salazar’s crew from their imprisonment within the Devil’s Triangle. Carina learns Henry is looking for the Trident’s location and offers to help him using a diary left by her unknown father. Carina and Jack are both captured and face execution, but are saved by Henry and Jack’s crew, setting sail on the Dying Gull.

text: Carina deciphers that the stars will lead to an island where the Trident is hidden. Salazar destroys Captain Barbossa’s fleet, but Barbossa manages to talk his way out of being killed by offering to help him find Jack, to which Salazar agrees. He tells Barbossa that long ago he worked for the Spanish Navy hunting down pirates. However, a young Jack tricked him into sailing into the Devil’s Triangle, cursing his crew. Salazar pursues the Dying Gull, forcing Jack, Henry, and Carina to flee to an island while fighting off Salazar's cursed sharks, discovering that Salazar’s crew cannot go on land. After saving Jack from a forced marriage, Barbossa allies himself with Jack and provides him his compass, obtained from the sea witch Shansa. He uses the Sword of Triton to restore the miniaturized Black Pearl, trapped in a bottle by Blackbeard, to its original size but betrays Jack and takes the Pearl for himself once more.

text: During the voyage, Jack and Barbossa realize Carina is the latter’s long-lost daughter. Barbossa had left her at an orphanage with his diary so she could live a better life. Approaching the Trident’s island, the Pearl evades a British Navy warship, which is destroyed by the Silent Mary before the Pearl runs aground on the island. Jack, Barbossa, and Carina use the island's magic to open a path to the Trident’s spot on the ocean floor, parting the ocean. Salazar captures Henry and possesses his body, chasing Jack and the others across the ocean floor and seizes the Trident, freeing Henry. Henry shatters the Trident, breaking all curses upon the sea and restoring Salazar’s crew to life.

text: However, the divided sea begins to collapse in on itself. The Pearl drops its anchor to lift them to safety, but Salazar, not satisfied with being human, follows Jack, still hell-bent on killing him. Carina realizes that Barbossa is her father when she spots a tattoo on his arm identical to the diary’s cover. Barbossa sacrifices himself to kill Salazar, allowing the others to escape alive. Some time later, Henry and Carina reach Port Royal, where Will appears, free from the Dutchman. His wife, Elizabeth, appears moments later and the Turner family reunites. Jack watches from the Pearl, sailing away into the horizon.

text: In a post-credits scene, Will and Elizabeth sleep in their bedroom but the resurrected Davy Jones appears. Will wakes up, assuming it was a nightmare, but a small puddle filled with barnacles under the bed reveals that Jones has returned as Jones is heard walking away.

text: Cast[edit]

text:
Johnny Depp as Captain Jack Sparrow:[11] The eccentric but noble pirate captain of the Black Pearl on the hunt for the Trident of Poseidon, which bestows control over the seas. In the film, according to director Joachim Rønning, Jack has "lost his mojo; he can't even be on the water". Rønning stated that Sparrow's role in the film mirrors his role in the original: "it was important to go back to the same dynamic that the first film had where Jack is not the main character. I wanted a story about real people, real characters – and then Jack Sparrow comes in and crashes the party every now and then",[12] and called Depp "a comedic genius, he has a comedic timing that I've never seen in anyone".[13] The film goes into the backstory of Sparrow, with the young Sparrow portrayed by Anthony De La Torre,[14] whose face was replaced by a CGI replica of Depp as he looked in 21 Jump Street and What's Eating Gilbert Grape.[15] Co-director Rønning believed de-aging Depp was tricky in terms of "trying to give him a backstory and still honour the mythology of the franchise".[16]
Javier Bardem as Captain Armando Salazar: A powerful and maniacal undead pirate hunter of the Spanish Navy who was trapped in the Devil's Triangle. After escaping, he seeks the Trident of Poseidon to wipe out all piracy and exact revenge on his old enemy, Captain Jack Sparrow.[1] Bardem set out to imbue the character with "a rage based on dented pride", comparing the character to "a wounded bull", owing to his spectacular fall from grace, going from a high ranking commander of a Spanish fleet to being betrayed and trapped in hell by Sparrow, who Bardem says is the reason for Salazar "holding that revenge in his body for eternity".[17] It took three hours a day to apply the make-up to Bardem's face, with Bardem referring to the process as having "cold chicken breasts" glued to his face.[18]
Geoffrey Rush as Captain Hector Barbossa:[19] The one-legged pirate captain of the Queen Anne's Revenge, former captain of the Black Pearl, and Captain Jack's former rival-turned-ally. In the film, Barbossa has become extremely wealthy since the previous film, with Rush referring to him as a "corporate pirate", having amassed a fleet of ships under his command and encrusted his peg-leg with jewels.[20]
Brenton Thwaites as Henry Turner:[21][1] The son of Will Turner and Elizabeth Swann-Turner, who tries to reconnect with his father. He struggles to break a curse that is preventing him from doing so.[22] The directors were keen to draft a new protagonist relationship, different to the two relationships explored in On Stranger Tides, with Henry and Carina, stating that "in the middle of a big action scene, you need to be able to lean on the characters and find the heart of that story, and channel the characters' vulnerability". Rønning noted that identity is a major theme in the film and to Henry and Carina's story arc: "they are on a similar quest and find common ground in looking for who they are".[13] Lewis McGowan portrays a young Henry.[23]
Kaya Scodelario as Carina Smyth (née Barbossa):[1] A headstrong, altruistic astronomer. Scodelario explained the character's motivation and role saying, "she is an academic, she's fighting for the right to study at university because women couldn't at that time. So she's on her own journey—looking for the trident of Poseidon—and she has a diary with clues."[24] She discussed the difference between Carina and Elizabeth Swann, believing that she was not just a carbon copy of that character.[25] For the directors, it was important to "modernise it with Henry and Carina, Kaya, especially brought that with her. She's a modern woman."[12] Scodelario worked with Nathanson to ensure the character was unique to the series and prevent her from being a "Mary Sue archetype", saying that "she's got her flaws…that's such an important thing to include when building a character, especially female characters, who often fall into two camps; they are either pretty and perfectly put together or completely insane. Carina has definitely got a little bit of both."[17]
Kevin McNally as Joshamee Gibbs:[1] Captain Jack's loyal friend and First Mate.
Golshifteh Farahani as Shansa:[1] a sea-witch and ally of Captain Barbossa.
David Wenham as Lieutenant John Scarfield: the second antagonist of the film and a British Royal Navy officer, who commands the HMS Essex.[26]
Stephen Graham as Scrum:[1] a member of Jack Sparrow's crew and former member of Blackbeard's crew.
Martin Klebba as Marty:[27] A member of Jack Sparrow's crew.
Giles New and Angus Barnett as Murtogg and Mullroy: Former Royal Marines turned pirates, who serve as Barbossa's right-hand men on board the Queen Anne's Revenge.[27]
Orlando Bloom as Captain William "Will" Turner Jr.: a blacksmith-turned-pirate, who was transformed into the Captain of the Flying Dutchman at the end of At World's End. Speaking about his possible return to the franchise, Bloom stated that he would love to portray a character outside of his usual role types as a good-looking hero: "Of course, I'm Davy Jones now, so I'm down the bottom of the ocean. It might be kind of fun to do something where I'm rumbling 'round the bottom of the ocean, because I won't look anything like me. [Gestures to his face] Get all gnarly."[28]

tag: ul

text: Additionally, Keira Knightley briefly appears at the end and reprises her role in the film series as Elizabeth Swann,[29] Will Turner's wife, and Henry's mother. Adam Brown, Danny Kirrane, and Delroy Atkinson appear as members of Jack's crew. In the prison scene, Paul McCartney appears briefly as Jack's paternal uncle, Uncle Jack.[30][27][30][30][31][32] Alexander Scheer plays a young Captain Edward Teague in a flashback sequence, while Keith Richards' likeness (as Jack's father) was also used.[33] A silhouette of Davy Jones, one of the series' former villains, was seen in the post-credits scene, but no actor was credited for this appearance. Pablo and Chiquita reprised their role as Jack the Monkey.

text: Production[edit]

text: Development[edit]

text: Shortly before the release of On Stranger Tides in 2011, the cast and crew of the fourth film were told to set aside time in the near future, as Walt Disney Pictures intended to shoot a fifth and sixth film back-to-back (like the first two sequels).[34] However, it was later stated that only a fifth film was in the works. On January 11, 2013, Jeff Nathanson signed on to write the script for the film.[35] Rob Marshall, the director of the last film, was believed for return to direct,[36] but he declined after he chose to direct Into the Woods[37] (2014) and The Thin Man[38] (both projects for Disney and starring Johnny Depp). After Marshall passed on the project, many directors were rumored to direct the film, like Tim Burton, Sam Raimi, Shawn Levy, Chris Weitz, Alfonso Cuarón and Gore Verbinski (who directed the first three films).[39] On May 9, 2013, it was reported that Fredrik Bond, Rupert Sanders, and the Norwegian film duo Joachim Rønning and Espen Sandberg were considered to direct the fifth film.[40] Finally, on May 29, 2013, Rønning and Sandberg were selected to direct.[41] This decision was based both on their Academy Award-nominated high sea film Kon-Tiki, as well as their ability to work with a limited budget.[42] Geoffrey Rush argued that the pair brought "a kind of Euro sensibility to traditional Hollywood franchise thinking".[43] While Orlando Bloom believed that they'd "recaptured the simplicity and charm", calling the film "fantastic, really entertaining".[44] On August 22, 2013, Rønning and Sandberg revealed that the title of the fifth film would be Dead Men Tell No Tales.[45] They also confirmed that they were working on the film, speaking highly of Jeff Nathanson's "funny and touching" script and that they are inspired by the first film, The Curse of the Black Pearl,[6] stating that the original is "scary, it's funny, and most of all it's a comedy, but with great heart, and that structure and the dynamics between the characters was something I really wanted to try and reinvent". On the pair's decision to direct the film, Rønning believed that "it was all there in this script already, and for me, it was just a matter of adding scenes that carry the tradition of Gore Verbinski, bring the emotional core and big action set pieces", with Charlie Chaplin and Buster Keaton also being in the director's mind when crafting the tone of the film.[13] The pair also wanted to include two things new to the series: "it needs to have heart; I really believe this to be the most emotional Pirates yet", argued Rønning, as well as exploring the roots of Jack Sparrow.[46] Kaya Scodelario felt that the film "will have much more of the feel of the first film, the producers want to take it back to the beginning again. They wanted it to have this epic journey, and for it to make sense, and for it to tie things up, and also lead to new storylines."[7]

text: However, after Disney's The Lone Ranger lost the studio $190 million in 2013—a film also starring Depp in a similarly eccentric role—Disney questioned the bankability of Depp and thus the franchise, so the film was reconsidered and not actually green-lit as of early 2014.[47] Another problem, along with the lack of success Depp experienced outside of the Pirates franchise were script problems, as Walt Disney Studios chairman Alan Horn stated: "We haven't seen a screenplay yet that I've been able to sign off on. There are a lot of variables that affect the final outcome once it leaves the studio lot, so we are very careful."[48] Due to these problems, the film's production was delayed, and it moved from a 2015 release aspired by Disney in 2013[35] to a likely release in 2016.[49] Producer Jerry Bruckheimer revealed that script as well as budget issues were behind the delay, and that Jeff Nathanson was at work on a second attempt based on a well-received outline, stating: "It's all a factor. We want a script that everyone's signed off on and a budget that everyone's signed off on."[42] After the script was accepted and the film was finally officially green-lit by Disney in July 2014, the release date moved to July 7, 2017.[50]

text: Many of the crew members for the film were new to the franchise, replacing members that had served on the previous four films. Apart from directors Rønning and Sandberg and writer Nathanson, a new director of photography, Paul Cameron replaced Dariusz Wolski, production designer Nigel Phelps, visual effects supervisor Gary Brozenich, special effects supervisor Dan Oliver, supervising stunt coordinator R. A. Rondell, stunt coordinators Thomas Robinson Harper and Kyle Gardiner, makeup and hair designer Peter Swords King, executive producers Joe Caracciolo Jr. and Brigham Taylor replacing Mike Stenson, film editors Joel Cox, Gary D. Roach and Roger Barton and composer Geoff Zanelli taking over from composer of the primary themes for the series, Hans Zimmer. Costume designer Penny Rose returned after providing the costumes for all four previous films, along with executive producer Chad Oman.[1][51][52]

text: Speaking to IGN while promoting The Hobbit: The Battle of the Five Armies, Orlando Bloom indicated that the film might serve as a soft reboot for the franchise, saying: "Basically, they want to reboot the whole franchise, I think, and do something with me and the relationship with my son."[28]

text: Writing[edit]

text: By 2011, shortly before the release of On Stranger Tides, Terry Rossio was writing a script for a fifth film without his partner Ted Elliott.[53] Rossio's draft was ultimately rejected. "My version of Dead Men Tell No Tales was set aside because it featured a female villain," recalled Rossio, "and Johnny Depp was worried that would be redundant to Dark Shadows, which also featured a female villain."[54] In January 2013, Disney hired Jeff Nathanson to work on a script.[35] That September, producer Bruckheimer said, "We have an outline everyone loves but the script is not done," explaining that the release would be postponed beyond summer 2015.[42]

text: On April 13, 2014, Depp said Bruckheimer and Disney had invited him in to collaborate with the writer Jeff Nathanson, noting:

text: Everyone involved wants the script to be right and perfect. So we have gone on to do other things [in the meantime]. We are still going to do the film together. I enjoy them immensely. They are super talented. They have a great sense of humor. I think they have a really fun approach to what we are going to do with the next Pirates. Very happily and proudly, I have welcomed taking part in the story and working directly with the screenwriter [Jeff Nathanson]—he and I. It's working out really well that way. So I have high hopes for that Pirates 5 because if that's really the last one, which it probably is, I feel that we owe it to the audience who went and saw the films so many times. We'll do it right and end it on a high note.[55]

text: Casting[edit]

text: Speaking at the On Stranger Tides press launch in Cannes, Depp said he would play the role for as long as it is popular with the public.[56] In August 2012 news surfaced that Johnny Depp signed on officially for the fifth film, earning A$90 million to reprise his role.[11] As with the fourth film, Depp was also involved in scripting and planning Dead Men Tell No Tales.[55] Geoffrey Rush had commented on returning as Hector Barbossa in the fifth installment, saying "If they keep shapeshifting this character, absolutely" as well as implying he may return as the villain.[57] He also said that Barbossa's megalomania "could explode in horrific ways".[58] In December 2014, Rush confirmed his return for the fifth installment, where Barbossa and Jack were "at the heart of it and there's a whole new set of story lines".[19] In late 2011, about four years after choosing not to return for the fourth installment, Orlando Bloom stated that he would like to return for the fifth film if he was offered.[59] On May 11, 2011, Naomie Harris expressed her desire to return as Tia Dalma if they called her.[60] Several weeks after Disney officially green-lit the film, Bloom stated that there were "discussions" about his return to the franchise in September 2014.[61] Bloom further commented in December 2014, that while he was not sure whether he would return, there were talks. He also indicated that Disney could do a soft reboot with the franchise and focus on Will Turner and his son.[28] After months of speculation and after filming wrapped up, Bloom's participation was confirmed at Disney D23 on August 15, 2015.[62]

text: On December 2, 2013, it was reported that Christoph Waltz was in talks to appear as the film's main antagonist,[63] but he finally declined. Australian actor Brenton Thwaites entered talks for the role of Henry in late November 2014,[64] after Disney chose him over Taron Egerton, George MacKay, Mitchell Hope, Ansel Elgort and Sam Keeley.[65] In mid-January 2015, he stated that he was to travel to Australia for the film in February, disclosing that his role was indeed that of Will Turner's son, struggling to break a curse to meet his father.[22] The shortlist of actresses for the female lead consisted of Gabriella Wilde, Kaya Scodelario, Alexandra Dowling, Jenna Thiam and Lucy Boynton. On January 24, Jerry Bruckheimer announced via Twitter that Scodelario had won the role.[66] In July, her character was revealed to be called Carina.[67] In earlier drafts of the script the name Carina Smyth appeared as Barbossa's daughter and was a love interest of Sparrow's and was an astronomer accused of being a witch.[68] Scodelario confirmed that the character was an astronomer and that "she's a totally different character" to Keira Knightley's Elizabeth Swann, and also confirmed that Smyth will be Henry's love interest instead of Jack's.[25][69] By October 2014, Javier Bardem, husband of Penélope Cruz (who portrayed Angelica in the fourth installment), was in early talks to appear as the antagonist of the film.[70] His role was eventually confirmed to be that of Armando Salazar, who in early scripts was referred as Captain John Brand.[1] However, during an interview with Collider in 2012, Penélope Cruz stated that she would most likely not reprise her role as Angelica Teach.[71] Kevin McNally confirmed his return as Joshamee Gibbs via Twitter in late January.[72] Shortly after on location pre-production opened in Australia, Disney issued a casting call to local agents for actors from all age- and experience levels to apply for roles and as extras in the upcoming film, with casting also open in the US.[73] Adam Brown, Delroy Atkinson, Danny Kirrane were revealed as cast members shortly before filming.[30] Martin Klebba confirmed his return as Marty via Twitter days before filming began.[74] On February 17, 2015, Stephen Graham revealed that he will reprise his role as Scrum.[75] On September 24, 2015, a YouTube video was uploaded stating that Giles New and Angus Barnett would reprise their roles as Murtogg and Mullroy.[76] Director Joachim Rønning's two children appear in the film as extras.[77] Also, Keith Richards expressed interest in reprising his role as Captain Teague.[78] Additionally, Greg Ellis expressed interest in reprising his role as Theodore Groves, despite his character's apparent death in the previous film, saying the possibility that Groves survived.[79] Apart from this declaration, reports that a deceased Navy officer will star in the film, had sparked many rumors regarding the possibility of the return of James Norrington (portrayed again by Jack Davenport), who died in the third film.[80]

text: Both Lee Arenberg and Mackenzie Crook commented on the possibility of returning as Pintel and Ragetti. Arenberg confirmed in several interviews that, despite wanting to return to the fourth film,[81] he hoped to reprise his role as Pintel.[82] In an interview on November 7, 2014, Crook confirmed that he had received a call of availability from Disney for the film, although stated that he was uncertain about whether he wanted to reprise his role.[83] Crook declined to reprise his role ultimately, in order to focus on his television series Detectorists.[84] He said he felt "pangs of nostalgia" when the cast and crew filmed the film without him.[85] Furthermore, shortly before filming started, Arenberg announced on Twitter that he would not reprise his role as well, despite having been interested in doing so.[86] In early 2017, there were rumors that Keira Knightley was back to the franchise for a cameo scene despite Knightley saying in 2011 that she wasn't coming back to any future films. On April 18, 2017, the international trailer was released, confirming Knightley's participation.[87]

text: Filming[edit]

text: On January 15, 2014, directors Joachim Rønning and Espen Sandberg confirmed that shooting would take place in Puerto Rico and New Orleans[88] and Bruckheimer had previously mentioned that there might be a sequence in Louisiana.[89] However, a spokesman for the Australian Arts Minister George Brandis confirmed that the fifth installment was set to shoot exclusively in Australia after the government agreed to repurpose $20 million of tax incentives originally intended for the remake of 20,000 Leagues Under the Sea, thus edging out Mexico and South Africa as filming locations.[90] According to Australian film industry sources, on location pre-production started in late September 2014 and its cost is around $250 million.[91] This was officially confirmed by Disney and the Queensland Arts Minister on October 2, 2014, stating that filming will take place exclusively in Queensland, Australia, being the largest production to ever shoot in the country. Village Roadshow Studios and Port Douglas were officially confirmed as filming locations.[92] On January 1, 2015, The Rainbow Gypsy, a 15-year-old replica of an 1897 Scottish bawley, sailed into the Gold Coast to start the extensive refit, which will include a new bowsprit and reconfigured decks and cabins in order to become the Dying Gull, a single-masted ghost ship. Its captain and owner Kit Woodward was a rigger on the film.[93]

text: Filming commenced on February 17, 2015.[1] Ship scenes were filmed in front of a giant outdoor greenscreen in Helensvale,[94] while a film set in the form of a village was built in Maudsland.[95] Given the greenscreens were so tall they blocked sunlight, containers with inflatable bluescreens mounted on top were added to the set to allow for light to creep in.[96] While an initial draft of the script featured six ships, the end product had 11 vessels, meaning that to cut costs, most of them were not full sets, but partial constructs later enhanced by computer graphics, at times built atop an hydraulic rig to mimic the movement of seafaring while still on land. The camera crew also made extensive use of drones to capture immersive views on sea without resorting to aerial footage or cranes.[15][97]

text: Filming moved to Doug Jennings Park on The Spit from March 30 to June 15, 2015 for water bound scenes.[98] However, due to extreme sea sickness among the cast and crew due to "big swells" at The Spit, filming moved to Raby Bay for calmer waters.[99][100] Scenes were shot at Byron Bay on June 1. Locals made up more than 75 percent of the 850-plus crew then working on the film.[101] After much speculation about whether Orlando Bloom would return, Bloom arrived at the Gold Coast in late May to reprise his role as Will Turner.[102][103] Scenes featuring a skeleton of a sperm whale that had been constructed were shot at Hastings Point from June 21 to 23.[104]

text: A number of issues and controversies set back the film during its production. The biosecurity laws in Australia posed problems regarding the capuchin monkeys that portray Hector Barbossa's pet monkey Jack, as the animals are regarded as a category 1 pest and require strict requirements and a 30-day quarantine.[105] Further controversy surrounding the use of the monkeys erupted from animal rights activist groups, who urged the Federal Environment Minister Greg Hunt to reject the application to fly two capuchin monkeys from California to Australia, arguing that the trip would "harm the monkeys' health, that movie performances are unnatural for wild creatures and that the appearance of monkeys in films encourages the illegal wildlife trade".[106] One of the monkeys caused further disruption when it wandered off set at Movie World and bit a make up artist on another production on the ear.[107] Crew and cast members were forced to cover the camera lenses on all mobile phones with duct tape to prevent the film from being pirated before its release. To prevent fans from interfering with the production, secret filming locations used the production name of "Herschel" to hide the fact it was the fifth Pirates of the Caribbean film.[108] Following the attempt of an armed man trying to bypass security, the already tight security was increased.[109]

text: On March 10, 2015, Depp was injured off set and had to be flown back to the United States for surgery.[110] Due to his absence, filming stalled completely and 200 crew members were forced to stand down for two weeks as they had done all they had been able to without Depp.[111] Filming was set to resume "on or about April 20"[112] and Depp returned to set on April 21.[113] In June, Kaya Scodelario was injured on set along with a stuntman.[114]

text: Most of the cast and crew had finished on the July 8, 2015, and a wrap party was held on July 11.[115] Filming then moved to the Whitsundays for the final shots to be filmed.[67][116] On July 21, 2015, Joachim Rønning announced via Instagram that filming has wrapped after a 95-day shoot.[117] After nearly a year in post production, reshoots and additional photography was conducted in Vancouver, Canada from March 24 to April 13, 2016 under the production title "Herschel Additional Photography".[118]

text: The entire film was filmed in IMAX for an expanded 1.9:1 aspect ratio, giving IMAX screenings of the film 26% more picture on the screen.[119]

text: Music[edit]

text: For the first time in the series since Pirates of the Caribbean: The Curse of the Black Pearl (which he co-wrote with Klaus Badelt), Hans Zimmer is not composing the music for the film. Instead, one of his protégés, Geoff Zanelli, who worked on all previous four installments in the franchise, is the main composer for the film.[120] Zanelli said of taking over from Zimmer as composer for the series, "What Hans did for the Pirates movies redefined the sound of the entire genre, it has been very fulfilling to work alongside him and [producer] Jerry [Bruckheimer] on the past four films. Dead Men Tell No Tales enlarges the Pirates universe with many new, unique elements, and I'm building a distinctive sound for this film that springboards off of many years of collaborating in the Pirates world."[52] The film's soundtrack was released on May 26, 2017.[121]

text: Post-production[edit]

text: Work on the film concluded on April 19, 2017.[122] Eight companies handled the film's 2,000 visual effects shots, with 150 of them consisting only of computer graphics. The primary vendor was Moving Picture Company, from which hails the film's overall effects supervisor Gary Brozenich.[96] Among MPC's work was Salazar's pirates, whose on-set footage filmed against a blue screen was mostly replaced by CGI given all have missing parts of their body as well as floating hair and clothing, with Brozenich stating that was kept of the original actors was "their run, gait and faces." To provide reference for the floating parts, that was meant to resemble a perpetual drowning state, a stuntman in full costume and wig dove into a swimming pool, and was filmed underwater by both a GoPro and a Canon 5D doing various actions.”[15] Atomic Fiction handled the scenes of St. Martin, turning the few blocks of buildings built on set onto more than 600 CG buildings surrounded by a jungle environment environment combining references from both the Caribbean and Thailand, and enhancing through CGI both the guillotine on which Jack Sparrow is nearly executed and the bank from the heist scene, that was meant to look as if it was dragging through the ground instead of driving on top of it.[123] Along with sea footage filmed in both the Australian sets and Key West, Florida, there was extensive usage of water simulations, with the artists basing on the Beaufort scale to ensure the sea and wind was realistic.[96]

text: Release[edit]

text: Dead Men Tell No Tales had its world premiere at the Shanghai Disney Resort on May 11, 2017.[2] In several countries, the film was released as Pirates of the Caribbean: Salazar's Revenge, including English-speaking countries.[124] It was released at cinemas in Italy[125] and Norway[126] on May 24. The film was released in the United States, Canada, and China on May 26.[127] It is the first Hollywood feature to be released in the United States for the new panorama-like ScreenX format; it will play in two locations in the U.S.—CGV Buena Park and CGV Cinemas—both in Los Angeles, California. Additionally, it will play in 81 screens at select theaters in Korea, China, Thailand, Vietnam, Turkey and Indonesia. The film will also play in 4D on 373 4DX screens worldwide.[128] It is Disney's third wide release of the year following Beauty and the Beast and Guardians of the Galaxy Vol. 2.[129]

text: Marketing[edit]

text: A robust marketing effort helped promote Dead Men Tell No Tales.[130] The film was first showcased at the Disney D23 Expo 2015 where Depp appeared in costume as Jack Sparrow and the film's logo was revealed with Orlando Bloom confirmed to be starring in the film.[131][132] Elizabeth Rudnick has been self-confirmed to novelize the film, as well as describing the film as bringing back "sensibility" plus bringing back Jack Sparrow in "all of his swaggering glory".[133] Another book is set to be released by Disney, a tie-in prequel expanding the backstory of the character of Carina Smyth, titled Pirates of the Caribbean: Dead Men Tell No Tales – The Brightest Star in the North.[134] The film was also showcased at the Walt Disney Content Showcase in Africa in 2016 where concept art, story details and on set images were previewed.[135] The first teaser trailer was released on October 2, 2016, during Fear the Walking Dead and showcased Armando Salazar hunting for Jack Sparrow who doesn't appear in the trailer except only his image on a wanted poster.[136] On January 27, 2017, Disney uploaded an eight-second motion poster to their official Instagram account for the release of a TV spot of the film during Super Bowl LI.[137] Disney then released a 30-second television teaser at Super Bowl LI, with an extended version released online set to Johnny Cash's "Ain't No Grave". The trailer was considered to be the "big" trailer of the event and was the most viewed trailer of all the films advertised at the halftime show. A new teaser poster was also released with the trailer. Both teasers received a highly positive reaction from audiences.[138][139] The official trailer was released on March 2, 2017. Another trailer was released on March 25, 2017.[140] The first 30-second TV spot was released on March 31, 2017. On April 21, at Disney Parks and on the four Disney cruise ships, Disney previewed a sneak peek of the film.[141] With the release of Guardians of the Galaxy Vol. 2 on April 28, 2017 in the UK, Disney premiered a 5-minute extended sequence of the film in front of the Marvel film.[142][143]

text: Home media[edit]

text: Pirates of the Caribbean: Dead Men Tell No Tales was released on digital download by Walt Disney Studios Home Entertainment on September 19, 2017, and on Blu-ray, Ultra HD Blu-ray and DVD on October 3, 2017.[144] In its first week to sale were the top home media release. The Blu-ray version accounted for 78% of the sales. Meanwhile, the home video release of the new "Pirates" sequel helped bring previous films in the franchise back into the Blu-ray top 25, with 2011's On Stranger Tides at No. 12, 2007's At World's End at No. 19, and 2006's Dead Man's Chest at No. 20. The original film, 2003's Pirates of the Caribbean: The Curse of the Black Pearl, landed at No. 23.[145]

text: Hacking incident[edit]

text: In May 2017, the film was allegedly stolen by a group of piracy hackers, who demanded a large sum of money from Disney in order for them not to distribute the unreleased film. The company refused to do so and worked with the FBI in order to get the identity of the group.[146] Also Disney CEO, Bob Iger reported that hackers did not steal their movie.[147]

text: Reception[edit]

text: Box office[edit]

text: Pirates of the Caribbean: Dead Men Tell No Tales grossed $172.5 million in the United States and Canada and $622 million in other territories for a worldwide total of $794.2 million, against a production budget of $230 million.[4]

text: The film had a worldwide opening of $271.4 million from 55 markets, with $24 million coming from 1,088 IMAX screens.[148] The film's six-day opening gross pushed the franchise gross past the $4 billion mark.[149] Despite being the lowest-grossing film of the series in the US by nearly $70 million, the film became the highest-grossing entry of the Pirates franchise internationally when going by modern foreign-exchange rates, passing On Stranger Tides, which grossed $593.4 million at current rates.[150] Despite weak US totals, Deadline.com noted the film should turn a net profit of around $280 million after factoring together all expenses and revenues.[151]

text: North America[edit]

text: In April 2017, early projections had the film grossing $115 million over its four-day Memorial Day opening weekend.[152] In early May, projections were adjusted to $90–100 million, which was again lowered down to $80–85 million, with a chance of hitting $100 million, by the week of its release.[153] It was released in 4,276 theaters, of which over 3,100 were 3D, including 400 IMAX locations, over 500 Premium Large Format locations, 170 D-Box locations, 10 4D auditoriums and three venues featuring the ScreenX three-screen format.[154] It opened Friday, May 26, 2017, and earned $23.4 million on its opening day, including $5.5 million it made from Thursday night previews. Its opening day was the lowest of the franchise.[155] In total, it grossed $63 million over three days, and $78.5 million over four (Friday–Monday), finishing first at the box office ahead of Guardians of the Galaxy Vol. 2 and fellow newcomer Baywatch.[156][157] On a three-day basis, the film did 31% less than On Stranger Tides did over its first three days in 2011, after adjusting for inflation, and on a four-day basis, it was down 34% from At World's End and overall is the second-smallest debut of the franchise after the first film.[158] Despite the film registering the highest test score in the series' history,[159] the opening came in well below initial expectations, which was attributed to various reasons, such as Johnny Depp's diminishing returns and his depreciating public image amid his personal problems, the wave of negative reviews from critics (mainly on Rotten Tomatoes), franchise fatigue and the problem of Memorial Day weekend failing to attract considerable moviegoers in the past years. However, although the film's opening was below predictions, it wasn't considered a fatal failure and was better than Disney had for its last few Memorial Day releases (Prince of Persia: The Sands of Time, Tomorrowland and Alice Through the Looking Glass).[160][161][162] Studio executives said they were pleased with the movie's opening, both in the US and abroad.[149] Its opening further helped Disney push past $1 billion in the US to record the second-fastest time a studio has reached the mark in the US, second only to Disney's own record from 2016 when the studio surpassed $1 billion in early May.[163]

text: After dropping by 73% on its second Friday, the worst Friday-to-Friday drop in the series, the film fell by a total of 65% in its second weekend, also the worst of the series, grossing $22.1 million.[164] As a result, it finished in third place, after newcomers Wonder Woman ($103.3 million) and Captain Underpants: The First Epic Movie ($23.9 million).[165] It made $10.7 million in its third weekend, $9 million in its fourth and $5.2 million in its fifth, respectively, finishing 4th, 6th and 7th at the box office.[166][167]

text: Outside North America[edit]

text: Internationally, where it is marketed as Salazar's Revenge in many countries, the film was released day-and-date with its North American debut in 54 markets (91% of its total marketplace, except Japan, where it debuted on July 1).[168] Preliminary reports had the film opening to $150–175 million, but possibly overperforming depending on major markets, most notably China.[154][169] While its Chinese run benefited from the Dragon Boat Festival—a lucrative moviegoing period—from May 28–30 as well as from International Children's Day (June 1),[170][171] the 2017 Manchester Arena bombing had a deteriorating effect on certain European markets, and eased moviegoing admissions across the continent over the film's opening weekend.[172] From Wednesday to Friday, it registered an opening of $208.8 million. Around $14 million of that came from IMAX screenings, the second-biggest international IMAX opening in May only after Captain America: Civil War.[148] Similar to its US plunge, it earned $73.8 million in its second weekend, thus, falling in second place behind Wonder Woman.[173]

text: It recorded the biggest opening day of the year in several markets including Germany ($3.6 million), Austria, France ($2.3 million), Finland, Sweden, Belgium, Thailand ($400,000), Indonesia, Malaysia and the Netherlands ($900,000, also the second-biggest Disney bow, behind Star Wars: The Force Awakens), while Russia opened with $4 million, the fifth-biggest ever.[172][174] In terms of opening, Russia posted the biggest opening of all time with $18.4 million ($18.6 million including previews) while South Korea ($11.5 million), France ($9.1 million), Germany ($8.3 million), Mexico ($6.9 million), the UK ($6.1 million), Brazil ($5.6 million), Italy ($5.5 million), Australia ($4.4 million), Spain ($4.4 million), Indonesia ($4 million), Taiwan ($3.6 million), India ($3 million) and Argentina ($3 million) recorded the top openings.[148][163][175][176]

text: In China, where the film had its global premiere, it earned $21.3 million on its opening day, the fourth-biggest Disney opening day in the country. It had an 87% marketshare and had already surpassed the entire earnings of Pirates of the Caribbean: At World's End.[177] Earning a total of $67.9 million, it registered the third-highest three-day for any Disney title, only behind Captain America: Civil War and Avengers: Age of Ultron and a much higher opening than the U.S.[148] The film did extremely well in IMAX, earning $9 million from 401 screens from Friday to early Monday bookings. The robust opening has been attributed to the Dragon Boat Festival, as well as Depp's star power, the ubiquity of the franchise, the impact of the Shanghai Disneyland Park, which opened last year and good word of mouth—it has a score of 7.5/10 on reviews aggregator Douban, and 8.7/10 on top mobile ticketing platform Weying.[178][179]

text: The final market for the film to be released in was Japan (July 1), where it opened at Number 1, achieving the highest-grossing opening for a Western film of the year, earning $9.25 million over the July 1–2 weekend.[180] It remained at the number 1 spot at the box office for three weeks.[181]

text: The biggest earning markets so far are China ($172.3 million), followed by Japan ($55 million), Russia and the CIS ($40.7 million), where is the second-highest-grossing film ever, behind only Avatar, Germany ($31 million), France ($28.7 million) and U.K. ($25.1 million).[182] The film is the highest-grossing of the series internationally by modern-foreign exchange rates.[183]

text: Critical response[edit]

text: On Rotten Tomatoes, the film has an approval rating of 29% based on 230 reviews, with an average rating of 4.7/10. The site's critical consensus reads, "Pirates of the Caribbean: Dead Men Tell No Tales proves that neither a change in directors nor an undead Javier Bardem is enough to drain this sinking franchise's murky bilge."[184] On Metacritic, the film has a weighted average score of 39 out of 100, based on 45 critics, indicating "generally unfavorable reviews".[185] Audiences polled by CinemaScore gave the film an average grade of "A–" on an A+ to F scale.[186]

text: Mike Ryan of Uproxx criticized the convoluted plot and overabundance of characters, writing: "Pirates of the Caribbean: Dead Man Tell No Tales is practically incoherent. I’ve been trying to wrap my head around the 'plot,' but it's been futile. I've asked literally eight other people who saw this movie to answer a couple specific questions and no one has been able to do it."[187] Writing for Rolling Stone, Peter Travers called the film "bloated, boring, repetitive and draining" and gave it one star out of four, saying, "Abandon ship, audiences. Paying cash money to see Pirates of the Caribbean: Dead Men Tell No Tales is the equivalent of walking the plank."[188] Ignatiy Vishnevetsky of The A.V. Club wrote that the film returns "to the basic formula of the first three Pirates films directed by Gore Verbinski, in which Johnny Depp’s louche and campy Jack Sparrow played second banana to an insipid love story…the two romantic leads […] succeed only in making the shortest movie in the series seem just as long as the rest."[189] A. O. Scott of The New York Times said of the film, "Its pleasures are so meager, its delight in its own inventions so forced and false, that it becomes almost the perfect opposite of entertainment."[190] Michael O'Sullivan of The Washington Post remarked that the film was "loud, overstimulating and hard to take in all in one sitting", comparing it to a "vacation that you’ll need a vacation from."[191] Mick LaSalle of San Francisco Chronicle found the film to be "a jumble of half-baked impulses", with the film's directors "trying to pump air and passion into a stinking corpse of a franchise."[192]

text: Richard Roeper of Chicago Sun-Times gave the film 3 out of 4 stars, saying: "Dead Men works well enough as a stand-alone, swashbuckling comedic spectacle, thanks to the terrific performances, some ingenious practical effects, impressive CGI and a steady diet of PG-13 dialogue peppered with not particularly sophisticated but (I have to admit) fairly funny sexual innuendo."[193] Pete Hammond of Deadline.com praised the film, calling it "the most entertaining installment," giving credit to Directors Rønning and Sandberg for creating a "rollicking good time". He praised the visual effects, particularly Salazar and his crew, arguing that it should be in line to receive an Academy Award for Visual Effects. He also gave high praise to Bardem for being able to create such a "fully dimensional villain" under the layers of make-up and CGI, as well as Depp for keeping the film and franchise going.[194] Leah Greenblatt of Entertainment Weekly gave the film a 'B', praising the fun nature of the film as well as its visuals, calling it "gorgeously detailed swashbuckling nonsense," but wished that the script had taken more risks instead of following the formula used in previous films.[195] Ashley Esqueda of CNET gave the film a positive review, arguing it brought the franchise back to what made its first two installments so fun, and praised Depp's performance as "delightful as ever."[196] Brian Truitt of USA Today gave the film 3 out of 4 stars, saying "What was once a past-its-prime franchise seems to have found new life."[197] Mark Hughes of Forbes opined "Dead Men Tell No Tales isn't as good as the first three films, but it's better than the fourth film", adding "it has mostly good performances, and a couple of great ones. It has fantastic visual effects, lots of humor that works, a lighthearted feel and sense of fun, and many terrific action set pieces to make your eyeballs pop out."[198]

text: Accolades[edit]

text: The film was nominated for six Teen Choice Awards: Sci-Fi/ Fantasy Movie, Sci-Fi/ Fantasy Actor, Sci-fi/ Fantasy Actress, Sci-Fi Fantasy villain and Sci-Fi Fantasy Liplock.[199]

text: Sequel[edit]

text: Shortly before the release of On Stranger Tides, it was reported that Disney was planning to shoot the fifth and the sixth films back-to-back,[200] although it was later revealed that only the fifth film was in development. On March 4, 2017, director Joachim Rønning stated that Dead Men was only the beginning of the final adventure, implying that it would not be the last film of the franchise and that a sixth film could be realized.[201] The post-credit scene of Dead Men shows Will Turner, Elizabeth Swann, and Davy Jones, implying that Will and Elizabeth will be main characters again and Davy Jones would be the main antagonist in a sixth film.[202] In September 2017, producer Jerry Bruckheimer indicated that another Pirates sequel is still possible if Dead Men Tell No Tales does well in its home release.[203] In October 2017, Kaya Scodelario said that she was contracted to return for a sixth film.[204] Shortly after, it was announced that Joachim Rønning is being eyed to direct the film.[205]